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Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously...

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Autores principales: Geier, Christoph B., Ellison, Maryssa, Cruz, Rachel, Pawar, Sumit, Leiss-Piller, Alexander, Zmajkovicova, Katarina, McNulty, Shannon M, Yilmaz, Melis, Evans, Martin Oman, Gordon, Sumai, Ujhazi, Boglarka, Wiest, Ivana, Abolhassani, Hassan, Aghamohammadi, Asghar, Barmettler, Sara, Bhar, Saleh, Bondarenko, Anastasia, Bolyard, Audrey Anna, Buchbinder, David, Cada, Michaela, Cavieres, Mirta, Connelly, James A., Dale, David C., Deordieva, Ekaterina, Dorsey, Morna J., Drysdale, Simon B., Ehl, Stephan, Elfeky, Reem, Fioredda, Francesca, Firkin, Frank, Förster-Waldl, Elizabeth, Geng, Bob, Goda, Vera, Gonzalez-Granado, Luis, Grunebaum, Eyal, Grzesk, Elzbieta, Henrickson, Sarah E., Hilfanova, Anna, Hiwatari, Mitsuteru, Imai, Chihaya, Ip, Winnie, Jyonouchi, Soma, Kanegane, Hirokazu, Kawahara, Yuta, Khojah, Amer M., Kim, Vy Hong-Diep, Kojić, Marina, Kołtan, Sylwia, Krivan, Gergely, Langguth, Daman, Lau, Yu-Lung, Leung, Daniel, Miano, Maurizio, Mersyanova, Irina, Mousallem, Talal, Muskat, Mica, Naoum, Flavio A., Noronha, Suzie A., Ouederni, Monia, Ozono, Shuichi, Richmond, G. Wendell, Sakovich, Inga, Salzer, Ulrich, Schuetz, Catharina, Seeborg, Filiz Odabasi, Sharapova, Svetlana O., Sockel, Katja, Volokha, Alla, von Bonin, Malte, Warnatz, Klaus, Wegehaupt, Oliver, Weinberg, Geoffrey A., Wong, Ke-Juin, Worth, Austen, Yu, Huang, Zharankova, Yulia, Zhao, Xiaodong, Devlin, Lisa, Badarau, Adriana, Csomos, Krisztian, Keszei, Marton, Pereira, Joao, Taveras, Arthur G, Beaussant-Cohen, Sarah L., Ong, Mei-Sing, Shcherbina, Anna, Walter, Jolan E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer US 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700649/
https://www.ncbi.nlm.nih.gov/pubmed/35947323
http://dx.doi.org/10.1007/s10875-022-01312-7
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author Geier, Christoph B.
Ellison, Maryssa
Cruz, Rachel
Pawar, Sumit
Leiss-Piller, Alexander
Zmajkovicova, Katarina
McNulty, Shannon M
Yilmaz, Melis
Evans, Martin Oman
Gordon, Sumai
Ujhazi, Boglarka
Wiest, Ivana
Abolhassani, Hassan
Aghamohammadi, Asghar
Barmettler, Sara
Bhar, Saleh
Bondarenko, Anastasia
Bolyard, Audrey Anna
Buchbinder, David
Cada, Michaela
Cavieres, Mirta
Connelly, James A.
Dale, David C.
Deordieva, Ekaterina
Dorsey, Morna J.
Drysdale, Simon B.
Ehl, Stephan
Elfeky, Reem
Fioredda, Francesca
Firkin, Frank
Förster-Waldl, Elizabeth
Geng, Bob
Goda, Vera
Gonzalez-Granado, Luis
Grunebaum, Eyal
Grzesk, Elzbieta
Henrickson, Sarah E.
Hilfanova, Anna
Hiwatari, Mitsuteru
Imai, Chihaya
Ip, Winnie
Jyonouchi, Soma
Kanegane, Hirokazu
Kawahara, Yuta
Khojah, Amer M.
Kim, Vy Hong-Diep
Kojić, Marina
Kołtan, Sylwia
Krivan, Gergely
Langguth, Daman
Lau, Yu-Lung
Leung, Daniel
Miano, Maurizio
Mersyanova, Irina
Mousallem, Talal
Muskat, Mica
Naoum, Flavio A.
Noronha, Suzie A.
Ouederni, Monia
Ozono, Shuichi
Richmond, G. Wendell
Sakovich, Inga
Salzer, Ulrich
Schuetz, Catharina
Seeborg, Filiz Odabasi
Sharapova, Svetlana O.
Sockel, Katja
Volokha, Alla
von Bonin, Malte
Warnatz, Klaus
Wegehaupt, Oliver
Weinberg, Geoffrey A.
Wong, Ke-Juin
Worth, Austen
Yu, Huang
Zharankova, Yulia
Zhao, Xiaodong
Devlin, Lisa
Badarau, Adriana
Csomos, Krisztian
Keszei, Marton
Pereira, Joao
Taveras, Arthur G
Beaussant-Cohen, Sarah L.
Ong, Mei-Sing
Shcherbina, Anna
Walter, Jolan E.
author_facet Geier, Christoph B.
Ellison, Maryssa
Cruz, Rachel
Pawar, Sumit
Leiss-Piller, Alexander
Zmajkovicova, Katarina
McNulty, Shannon M
Yilmaz, Melis
Evans, Martin Oman
Gordon, Sumai
Ujhazi, Boglarka
Wiest, Ivana
Abolhassani, Hassan
Aghamohammadi, Asghar
Barmettler, Sara
Bhar, Saleh
Bondarenko, Anastasia
Bolyard, Audrey Anna
Buchbinder, David
Cada, Michaela
Cavieres, Mirta
Connelly, James A.
Dale, David C.
Deordieva, Ekaterina
Dorsey, Morna J.
Drysdale, Simon B.
Ehl, Stephan
Elfeky, Reem
Fioredda, Francesca
Firkin, Frank
Förster-Waldl, Elizabeth
Geng, Bob
Goda, Vera
Gonzalez-Granado, Luis
Grunebaum, Eyal
Grzesk, Elzbieta
Henrickson, Sarah E.
Hilfanova, Anna
Hiwatari, Mitsuteru
Imai, Chihaya
Ip, Winnie
Jyonouchi, Soma
Kanegane, Hirokazu
Kawahara, Yuta
Khojah, Amer M.
Kim, Vy Hong-Diep
Kojić, Marina
Kołtan, Sylwia
Krivan, Gergely
Langguth, Daman
Lau, Yu-Lung
Leung, Daniel
Miano, Maurizio
Mersyanova, Irina
Mousallem, Talal
Muskat, Mica
Naoum, Flavio A.
Noronha, Suzie A.
Ouederni, Monia
Ozono, Shuichi
Richmond, G. Wendell
Sakovich, Inga
Salzer, Ulrich
Schuetz, Catharina
Seeborg, Filiz Odabasi
Sharapova, Svetlana O.
Sockel, Katja
Volokha, Alla
von Bonin, Malte
Warnatz, Klaus
Wegehaupt, Oliver
Weinberg, Geoffrey A.
Wong, Ke-Juin
Worth, Austen
Yu, Huang
Zharankova, Yulia
Zhao, Xiaodong
Devlin, Lisa
Badarau, Adriana
Csomos, Krisztian
Keszei, Marton
Pereira, Joao
Taveras, Arthur G
Beaussant-Cohen, Sarah L.
Ong, Mei-Sing
Shcherbina, Anna
Walter, Jolan E.
author_sort Geier, Christoph B.
collection PubMed
description Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10875-022-01312-7.
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spelling pubmed-97006492022-11-27 Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients Geier, Christoph B. Ellison, Maryssa Cruz, Rachel Pawar, Sumit Leiss-Piller, Alexander Zmajkovicova, Katarina McNulty, Shannon M Yilmaz, Melis Evans, Martin Oman Gordon, Sumai Ujhazi, Boglarka Wiest, Ivana Abolhassani, Hassan Aghamohammadi, Asghar Barmettler, Sara Bhar, Saleh Bondarenko, Anastasia Bolyard, Audrey Anna Buchbinder, David Cada, Michaela Cavieres, Mirta Connelly, James A. Dale, David C. Deordieva, Ekaterina Dorsey, Morna J. Drysdale, Simon B. Ehl, Stephan Elfeky, Reem Fioredda, Francesca Firkin, Frank Förster-Waldl, Elizabeth Geng, Bob Goda, Vera Gonzalez-Granado, Luis Grunebaum, Eyal Grzesk, Elzbieta Henrickson, Sarah E. Hilfanova, Anna Hiwatari, Mitsuteru Imai, Chihaya Ip, Winnie Jyonouchi, Soma Kanegane, Hirokazu Kawahara, Yuta Khojah, Amer M. Kim, Vy Hong-Diep Kojić, Marina Kołtan, Sylwia Krivan, Gergely Langguth, Daman Lau, Yu-Lung Leung, Daniel Miano, Maurizio Mersyanova, Irina Mousallem, Talal Muskat, Mica Naoum, Flavio A. Noronha, Suzie A. Ouederni, Monia Ozono, Shuichi Richmond, G. Wendell Sakovich, Inga Salzer, Ulrich Schuetz, Catharina Seeborg, Filiz Odabasi Sharapova, Svetlana O. Sockel, Katja Volokha, Alla von Bonin, Malte Warnatz, Klaus Wegehaupt, Oliver Weinberg, Geoffrey A. Wong, Ke-Juin Worth, Austen Yu, Huang Zharankova, Yulia Zhao, Xiaodong Devlin, Lisa Badarau, Adriana Csomos, Krisztian Keszei, Marton Pereira, Joao Taveras, Arthur G Beaussant-Cohen, Sarah L. Ong, Mei-Sing Shcherbina, Anna Walter, Jolan E. J Clin Immunol Original Article Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10875-022-01312-7. Springer US 2022-08-10 2022 /pmc/articles/PMC9700649/ /pubmed/35947323 http://dx.doi.org/10.1007/s10875-022-01312-7 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Original Article
Geier, Christoph B.
Ellison, Maryssa
Cruz, Rachel
Pawar, Sumit
Leiss-Piller, Alexander
Zmajkovicova, Katarina
McNulty, Shannon M
Yilmaz, Melis
Evans, Martin Oman
Gordon, Sumai
Ujhazi, Boglarka
Wiest, Ivana
Abolhassani, Hassan
Aghamohammadi, Asghar
Barmettler, Sara
Bhar, Saleh
Bondarenko, Anastasia
Bolyard, Audrey Anna
Buchbinder, David
Cada, Michaela
Cavieres, Mirta
Connelly, James A.
Dale, David C.
Deordieva, Ekaterina
Dorsey, Morna J.
Drysdale, Simon B.
Ehl, Stephan
Elfeky, Reem
Fioredda, Francesca
Firkin, Frank
Förster-Waldl, Elizabeth
Geng, Bob
Goda, Vera
Gonzalez-Granado, Luis
Grunebaum, Eyal
Grzesk, Elzbieta
Henrickson, Sarah E.
Hilfanova, Anna
Hiwatari, Mitsuteru
Imai, Chihaya
Ip, Winnie
Jyonouchi, Soma
Kanegane, Hirokazu
Kawahara, Yuta
Khojah, Amer M.
Kim, Vy Hong-Diep
Kojić, Marina
Kołtan, Sylwia
Krivan, Gergely
Langguth, Daman
Lau, Yu-Lung
Leung, Daniel
Miano, Maurizio
Mersyanova, Irina
Mousallem, Talal
Muskat, Mica
Naoum, Flavio A.
Noronha, Suzie A.
Ouederni, Monia
Ozono, Shuichi
Richmond, G. Wendell
Sakovich, Inga
Salzer, Ulrich
Schuetz, Catharina
Seeborg, Filiz Odabasi
Sharapova, Svetlana O.
Sockel, Katja
Volokha, Alla
von Bonin, Malte
Warnatz, Klaus
Wegehaupt, Oliver
Weinberg, Geoffrey A.
Wong, Ke-Juin
Worth, Austen
Yu, Huang
Zharankova, Yulia
Zhao, Xiaodong
Devlin, Lisa
Badarau, Adriana
Csomos, Krisztian
Keszei, Marton
Pereira, Joao
Taveras, Arthur G
Beaussant-Cohen, Sarah L.
Ong, Mei-Sing
Shcherbina, Anna
Walter, Jolan E.
Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients
title Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients
title_full Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients
title_fullStr Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients
title_full_unstemmed Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients
title_short Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients
title_sort disease progression of whim syndrome in an international cohort of 66 pediatric and adult patients
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9700649/
https://www.ncbi.nlm.nih.gov/pubmed/35947323
http://dx.doi.org/10.1007/s10875-022-01312-7
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